Abstract
Temporomandibular joint disorders (TMD) consist of a heterogeneous group of conditions that present with pain in the temporomandibular joint (TMJ) region and muscles of mastication. This project assessed the role of connexin 43 (Cx43), a gap junction protein, in the trigeminal ganglion (TG) in an animal model for persistent inflammatory TMJ hyperalgesia. Experiments were performed in male and female rats to determine if sex differences influence the expression and/or function of Cx43 in persistent TMJ hyperalgesia. Intra-TMJ injection of Complete Freund's Adjuvant (CFA) caused a significant increase in Cx43 expression in the TG at 4 days and 10 days post-injection in ovariectomized (OvX) female rats and OvX females treated with estradiol (OvXE), while TG samples in males revealed only marginal increases. Intra-TG injection of interference RNA for Cx43 (siRNA Cx43) 3 days prior to recording, markedly reduced TMJ-evoked masseter muscle electromyographic (MMemg) activity in all CFA-inflamed rats, while activity in sham animals was not affected. Western blot analysis revealed that at 3 days after intra-TG injection of siRNA Cx43 protein levels for Cx43 were significantly reduced in TG samples of all CFA-inflamed rats. Intra-TG injection of the mimetic peptide GAP19, which inhibits Cx43 hemichannel formation, greatly reduced TMJ-evoked MMemg activity in all CFA-inflamed groups, while activity in sham groups was not affected. These results revealed that TMJ inflammation caused a persistent increase in Cx43 protein in the TG in a sex-dependent manner. However, intra-TG blockade of Cx43 by siRNA or by GAP19 significantly reduced TMJ-evoked MMemg activity in both males and females following TMJ inflammation. These results indicated that Cx43 was necessary for enhanced jaw muscle activity after TMJ inflammation in males and females, a result that could not be predicted on the basis of TG expression of Cx43 alone.
Highlights
Temporomandibular joint disorders (TMD) represent a diverse group of conditions accompanied by pain in the temporomandibular joint (TMJ) region and muscles of mastication
Connexin 43 (Cx43) expression is regulated in a sexually-dimorphic manner in other tissues [33, 34], no previous studies have determined if sex differences and/or estrogen status alter Cx43 expression and function in an animal model for TMJ hyperalgesia
Cx43 displayed a marked and sexdependent increase in Cx43 area at 4 days and 10 days after Complete Freund’s Adjuvant (CFA) [F(8,27) = 7.01, p < 0.001]. Both OvX and OvX females treated with estradiol (OvXE) groups displayed significant (p < 0.01) and similar increases in Cx43 staining after CFA, while Cx43 staining in CFA-treated males was not statistically different from sham males (p < 0.1)
Summary
Temporomandibular joint disorders (TMD) represent a diverse group of conditions accompanied by pain in the temporomandibular joint (TMJ) region and muscles of mastication. Connexin 43 and TMJ Hyperalgesia evidence of tissue or nerve damage [3, 4], results from more invasive diagnostic methods such as synovial fluid sampling [5] or jaw muscle microdialysis sampling [6, 7] suggest that TMD is characterized as a persistent mild inflammatory condition. Results from in vitro studies suggest that TMJ nociceptors are sensitized after local inflammation [17] and are further enhanced by estrogen treatment [18]. Other studies have shown that ion channels in TG neurons associated with nociception are upregulated by TMJ inflammation and further enhanced by elevated estrogen conditions [19, 20]. A key mechanism linking inflammation to sensitization of nociceptors involves activation of satellite glial cells (SGC), a class of non-neuronal cells that surround sensory neurons. Cx43 expression is regulated in a sexually-dimorphic manner in other tissues [33, 34], no previous studies have determined if sex differences and/or estrogen status alter Cx43 expression and function in an animal model for TMJ hyperalgesia
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